Rational Routes to Formyl-Substituted Chlorins

Abstract

Two distinct approaches have been developed for the synthesis of chlorins bearing formyl groups: (1) reaction of an acetal-substituted 1-acyldipyrromethane with 2,3,5,6-tetrahydro-1,3,3-trimethyldipyrrin to give upon hydrolysis a 5-formylchlorin; (2) Pd-mediated coupling of a bromochlorin with a one-carbon synthon (hydroxymethyl tributyltin or CO) to give a 13-, 15-, or 3,13-formylchlorin. The zinc chlorins exhibit long-wavelength peak absorption maxima ranging from 626 to 667 nm, indicating the wavelength tunability afforded by formyl substitution.

Formyl-substituted porphyrins have proved valuable for fundamental spectroscopic studies and as versatile synthetic intermediates.¹ Formyl-substituted chlorins have provoked interest owing to the distinct spectra provided by chlorophyll b, which contains a formyl group at the 7-position, versus chlorophyll a, which contains a 7-methyl group. The formyl group also provides a valuable site for synthetic elaboration of chlorins,^2-5 although the synthesis of formylchlorins has presented a number of challenges.

One popular synthetic approach has been to use chlorophyll b directly in derivatization processes, including formation of the imine,⁶ olefin,⁷ or the meso-carbon of an attached porphyrin.² A second approach has been to formylate an intact chlorin. This approach is largely restricted to simple substituted chlorins (e.g., β-octaethylchlorin^8,9 or meso-tetraarylchlorins¹⁰) so as to avoid formation of regioisomers, although one notable exception is the regioselective 20-formylation of selected naturally occurring chlorins.^8,11 A third approach entails the modification of naturally occurring chlorins such as chlorophyll a. Examples include (i) oxidation of a 3-vinyl group to give a 3-formyl species,¹² (ii) oxidation of an 8-vinyl group to give an 8-formyl species,¹³ (iii) rupture of the isocyclic ring followed by functional group transformations to give the 13-formylchlorin^12,14 or 15-formylchlorin,¹⁵ and (iv) derivatization of alkyl groups at the 8- or 12-positions.^5,16 The ability to place formyl groups at designated sites in chlorins would benefit from more versatile methods of synthesis, particularly methods that do not rely on naturally occurring chlorins as starting materials.

We recently prepared a family of chlorins bearing auxochromes at the 3- and 13-positions.^17,18 The chlorins were prepared by de novo synthesis and contained a geminal dimethyl group in the reduced ring to ensure stability toward adventitious oxidation. The substituents were introduced at the 3,13-positions because the transition that gives rise to the long-wavelength (Q_y) band is polarized along this axis. The auxochromes included phenyl, vinyl, TIPS-ethynyl, and acetyl, of which the acetyl group gave the most pronounced changes in the absorption spectra. The presence of a single acetyl group at the 13-position caused a 26 nm redshift, whereas 3,13-diacetyl substitution caused a 56 nm redshift. On the other hand, similar groups at the 15-position caused much smaller effects.¹⁹ Extension of this approach to synthetic chlorins bearing formyl groups at specific positions is of great interest because the formyl group is expected to be a more potent auxochrome than acetyl, ethynyl, or vinyl. Toward, this goal, we report herein two rational routes to chlorins that enable placement of formyl groups at designated sites, including the 5-, 13-, 15- and 3,13-positions.

Synthesis of a 5-Formylchlorin from an Acetal-dipyrromethane

The synthesis of a 5-formylchlorin was approached through use of a 1-acyldipyrromethane that contains a protected formyl group (1).²⁰ Other acetal-chlorins have been prepared by reduction of the corresponding porphyrin²¹ or from the formylchlorin.²² 1-Acyldipyrromethane 1 was treated with NBS²³ at –78 °C for 1 h to afford the corresponding 1-bromo-9-acyldipyrromethane (2) in 79% yield (Scheme 1). Reduction of 2 with NaBH₄ afforded the 1-bromo-dipyrromethane-9-carbinol (Eastern half). The latter was immediately subjected to condensation²³ with tetrahydrodipyrrin 3²⁴ (Western half) in the presence of TFA to obtain the tetrahydrobilene-a derivative, which upon oxidative cyclization gave the 5-acetal-substituted zinc chlorin 4 in 16% yield. The acetal group was hydrolyzed (and the zinc chlorin was demetalated) by treatment with TFA/H₂O in CH₂Cl₂, thereby affording the free base formylchlorin FbC-F⁵P¹⁰ in 84% yield. Treatment of FbC-F⁵P¹⁰ with Zn(OAc)₂·2H₂O afforded the zinc chelate ZnC-F⁵P¹⁰ in quantitative yield.

Scheme 1.

Synthesis of Formylchlorins from Bromochlorins

To more generally introduce formyl groups at various β-positions, we first investigated Stille coupling of a bromochlorin and hydroxymethyltributyltin^25,26 to give the corresponding hydroxymethylchlorin (Scheme 2). The zinc chelate of the 13-bromochlorin (ZnC-M¹⁰Br¹³)¹⁷ gave limited conversion upon refluxing with THF. Demetalation of ZnC-M¹⁰Br¹³ with TFA afforded the crude free base chlorin. Coupling of the latter and Bu₃SnCH₂OH in the presence of Pd(PPh₃)₄ in THF for 30 h gave the 13-hydroxymethylchlorin 5 in 51% yield. The oxidation of 5 with MnO₂ in toluene at room temperature afforded the 13-formylchlorin FbC-M¹⁰F¹³ in 91% yield. The free base formylchlorin FbC-T⁵M¹⁰F¹³ was obtained similarly (Scheme 2). A streamlined procedure including demetalation, Pd-coupling, and oxidation gave FbC-T⁵M¹⁰F¹³ in 47% yield starting from ZnC-T⁵M¹⁰Br¹³.

Scheme 2.

We next investigated the more direct method of Pd-mediated reductive carbonylation.^27,28 A short survey of conditions (solvent, palladium source, and amount of HCO₂Na) identified effective conditions. Thus, treatment of ZnC-M¹⁰Br¹³ (10 mM) with sodium formate (20 mM) in the presence of (PPh₃)₂PdCl₂ (20 mol%) and PPh₃ (20 mol%) in DMF at 108 °C under an atmosphere of CO afforded the 13-formylchlorin ZnC-M¹⁰F¹³ in 68% yield. This Pd-mediated carbonylation method was successfully applied to introduce the formyl group into the chlorin macrocycle at the 13-, 3,13-, and 15-positions (Table 1).

Table 1.

Scope of Pd-Mediated Carbonylation of Chlorins

Bromochlorin	R5	R15	R3	R13	Formylchlorin	R15	R3	R13	Yield
aZnC-M10Br13	H	H	H	Br	ZnC-M10F13	H	H	CHO	68%
bZnC-T5M10Br13	p-tolyl	H	H	Br	ZnC-T5M10F13	H	H	CHO	72%
aZnC-Br3M10Br13	H	H	Br	Br	ZnC-F3M10F13	H	CHO	CHO	52%
cZnC-T5M10Br15	p-tolyl	Br	H	H	ZnC-T5M10F15	CHO	H	H	35%

^aRef. 17.

^bRef. 29.

^cRef. 30.

Absorption Spectra of Formylchlorins

The absorption spectra of the formylchlorins (in toluene at room temperature) are summarized in Table 2. Three classes are noted: zinc chlorins bearing a 10-mesityl group (ZnC-M¹⁰ series); zinc chlorins bearing a 5-p-tolyl group and a 10-mesityl group (ZnC-T⁵M¹⁰ series); and various free base chlorins (FbC series). Selected absorption spectra of the ZnC-M¹⁰ series are shown in Figure 1 (see Supporting Information for additional spectra).

Table 2.

Spectral Properties of Chlorins.^a

Compoundb	λB (fwhm) in nm	λQy (fwhm) in nm	IB/IQc	Δυ (cm-1)d
ZnC-M10	405 (13)	606 (12)	4.3	---
ZnC-P10	405 (13)	605 (11)	4.1	---
ZnC-M10A13	418 (18)	632 (14)	2.1	680
ZnC-M10F13	418 (20)	634 (12)	2.2	730
ZnC-F5P10	425 (29)	650 (36)	6.2	1100
ZnC-F3M10F13	439 (20)	667 (17)	1.4	1500
ZnC-A3M10A13	436 (21)	662 (18)	1.5	1400
ZnC-T5M10	412 (13)	608 (11)	5.0	---
ZnC-T5M10F15	417 (16)	626 (20)	5.6	470
ZnC-T5M10F13	424 (15)	637 (13)	2.6	750
FbC-M10	400 (34)	637 (9)	2.7	---
FbC-P10	403 (34)	637 (9)	2.8	---
FbC-M10F13	414 (35)	659 (11)	1.9	520
FbC-T5M10F13	422 (36)	663 (11)	2.2	620
FbC-F5P10	416 (41)	672 (27)	5.0	820

^aIn toluene at room temperature.

^bAll compounds that are not synthesized herein are described in ref. 19.

^cRatio of the intensities of the B and Q_y bands.

^dThe redshift of the Q_y band relative to that of the parent chlorin (ZnC-M¹⁰, ZnC-T⁵M¹⁰ or FbC-M¹⁰).

Figure 1.

Absorption spectra (normalized) in toluene at room temperature of ZnC-M¹⁰ (trace a, λ_Qy 606 nm),¹⁷ZnC-M¹⁰F¹³ (trace b, λ_Qy 634 nm), ZnC-F⁵P¹⁰ (trace c, λ_Qy 650 nm), and ZnC-F³M¹⁰F¹³ (trace d, λ_Qy 667 nm).

The presence of a formyl group at the 3-, 5-, 13-, or 15-positions causes a redshift of the long-wavelength absorption (Q_y) band. However, the magnitude of the redshift, the sharpness of the Q_y band, and the intensity of the Q_y band relative to the band in the blue region (B band) depend on the position of substitution. The major observations are as follows:

1. A 13-formyl group causes a redshift of 730 cm^-1 (28 nm; ZnC-M¹⁰F¹³ versus ZnC-M¹⁰), to be compared with only 680 cm^-1 (26 nm) for the corresponding 13-acetylchlorin¹⁷ (ZnC-M¹⁰A¹³). The relative intensity of the Q_y band increases by approximately two-fold for ZnC-M¹⁰F¹³ versus ZnC-M¹⁰ while the sharpness (fwhm) remains relatively constant (12 nm). Note that the 10-mesityl and 10-phenyl groups give essentially identical spectra.¹⁹

2. 3,13-Diformyl groups cause a redshift of 1500 cm^-1 (61 nm; ZnC-F³M¹⁰F¹³ versus ZnC-M¹⁰), to be compared with 1400 cm^-1 (56 nm) for the corresponding 3,13-diacetylchlorin¹⁷ (ZnC-A³M¹⁰A¹³). A further increase in relative intensity of the Q_y band occurs (I_B/I_Q = 1.4 for ZnC-F³M¹⁰F¹³ versus 4.3 for ZnC-M¹⁰) while the sharpness (fwhm) decreases only modestly (17 nm).

3. A 5-formyl group causes a strong redshift of 1100 cm^-1 (44 nm; ZnC-F⁵P¹⁰ versus ZnC-P¹⁰), which is more pronounced than at any other single site examined herein. However, the Q_y band is relatively broad (fwhm = 36 nm).

4. A 15-formyl group causes a modest redshift of 470 cm^-1 (18 nm; ZnC-T⁵M¹⁰F¹⁵ versus ZnC-T⁵M¹⁰), band broadening (fwhm = 20 nm), and no increase in the relative intensity of the Q_y band (I_B/I_Q = 5.6 for ZnC-T⁵M¹⁰F¹⁵ versus 5.0 for ZnC-T⁵M¹⁰).

Thus, the formyl group is a slightly more potent auxochrome than the acetyl group at those positions where comparisons can be made (13- or 3,13-positions), causing bathochromic and hyperchromic effects without substantial band broadening. The bathochromic shift increases in order of positions 5 < 13 < 15, whereas the band-broadening effect increases in order of positions 13 < 15 < 5. Similar trends were noted in the free base chlorins where comparisons can be made.

In summary, we have developed rational approaches for the synthesis of formylchlorins. Pd-mediated formylation is attractive where suitable bromochlorins are available (positions 3, 13, 15, etc.), otherwise a complementary route entails construction of a chlorin with use of an acetal-substituted precursor (e,g., 5-position). Both approaches were successfully implemented to give milligram quantities of formylchlorins. The absorption spectra of zinc chelates of 5-, 13-, 3,13- and 15-formylchlorins revealed a significant effect of the formyl group depending on the position of substitution. The long-wavelength absorption band can now be tuned over the range of 606 – 667 nm. For applications in flow cytometry, the chlorins with distinct and sharp bands could provide a panel of fluorophores. For applications in solar energy conversion, the collection of wavelength-tunable chlorins, including the chlorins with broad bands, could provide enhanced solar coverage. Taken together, the routes described herein afford versatile access to formylchlorins for use in fundamental spectroscopic studies and further synthetic elaboration.

Experimental Section

Carbonylation Procedure: Zn(II)-3,13-Diformyl-17,18-dihydro-18,18-dimethyl-10-mesitylporphyrin (ZnC-F³M¹⁰F¹³)

Following a procedure for CO-mediated formylation,²⁸ a mixture of ZnC-Br³M¹⁰Br¹³ (13.8 mg, 0.0203 mmol), (PPh₃)₂PdCl₂, (2.85 mg, 0.00406 mmol, 20 mol%), PPh₃ (1.06 mg, 0.00406 mmol, 20 mol%) and sodium formate (3.50 mg, 0.0507 mmol) was dried in a Schlenk flask for 1 h. DMF (1.2 mL) was added, and CO gas was bubbled through the reaction mixture for 2 h at 108 °C. Then, the reaction mixture was heated at 108 °C under a balloon containing CO for 24 h. After cooling to room temperature, the reaction mixture was treated with CH₂Cl₂ and water. The organic layer was separated, washed (water, brine), dried (Na₂SO₄) and concentrated. The resulting residue was chromatographed [silica, hexanes/CH₂Cl₂ (1:2) → CH₂Cl₂ → CH₂Cl₂/ethyl acetate (7:1)] to afford a trace amount (∼5% of the total) of a mono-formylated chlorin followed by the title compound as a green solid (6.1 mg, 52%): ¹H NMR (300 MHz) δ 1.82 (s, 6H), 2.03 (s, 6H), 2.60 (s, 3H) 4.53 (s, 2H), 7.23 (s, 2H), 8.38 (d, J = 4.5 Hz, 1H), 8.62 (s, 1H), 8.87 (d, J = 4.5 Hz, 1H), 9.00 (s, 1H), 9.26 (s, 1H), 9.61 (s, 1H), 10.3 (s, 1H), 10.88 (s, 1H), 11.15 (s, 1H); ¹³C NMR δ 188.8, 188.7, 172.8, 167.4, 162.1, 161.5, 160.8, 144.0, 141.9, 140.2, 138.9, 137.9, 137.5, 135.8, 135.7, 131.9, 130.6, 128.2, 128.1, 110.3, 107.7, 98.3, 96.6, 94.5, 50.5, 44.3, 31.0, 21.4, 21.2; LDMS obsd 576.8; FAB-MS obsd 576.1499, calcd 576.1504 (C₃₃H₂₈N₄O₂Zn); λ_abs (toluene) 439, 667 nm.

Streamlined Procedure via Hydroxymethylation: 13-Formyl-17,18-dihydro-18,18-dimethyl-10-mesityl-5-p-tolylporphyrin (FbC-T⁵M¹⁰F¹³)

A sample of chlorin ZnC-T⁵M¹⁰Br¹³ (7.50 mg, 0.0108 mmol) was treated with TFA (25.0 μl, 0.324 mmol) in CH₂Cl₂ (1.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of a mixture of saturated aqueous NaHCO₃ and CH₂Cl₂. The organic layer was separated, washed (water, brine), dried (Na₂SO₄) and concentrated to afford the free base chlorin. Following a procedure for Stille coupling with chlorins,¹⁷ a mixture of free base chlorin (∼0.0108 mmol) and Pd(PPh₃)₄ (2.50 mg, 0.00216 mmol) was dried in a Schlenk flask for 30 min. Hydroxymethyltributyltin (13.8 mg, 0.0432 mmol) in THF (1.0 mL) was added, and the reaction mixture was refluxed for 30 h. The reaction mixture was concentrated. The resulting residue was dissolved in toluene (0.20 mL), and MnO₂ (47.0 mg, 0.540 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and chromatographed [silica, hexanes → hexanes/CH₂Cl₂ (1:1) → (2:8)] to afford a purple solid (3.0 mg, 47%) with characterization data (¹H NMR, ¹³C NMR, LD-MS, FAB-MS, UV-Vis) consistent with those for the product obtained via individual stepwise procedures (see Supporting Information).

Supplementary Material

1si20070515_12. Supporting Information.

Spectral data (absorption, ¹H NMR, LD-MS) for all new chlorins, and additional experimental procedures. This material is available free of charge via the Internet at http://pubs.acs.org.